Title: SARS: Systematic Review of Treatment Effects



Table S7. Results of Treatment within SARS Patients (English literature)

|Treatment of interest |Dose |Authors’ observations/inference |Critical appraisal |Conclusion |Reference ID |

|Ribavirin |Not available |Haemolytic anaemia: 67/110. Hypomagnesaemia: |Haemoglobin levels at admission and after treatment were |Possible harm |(1) |

| | |35/76. Authors conclude “adverse effects occur|compared. Frequent side effects such as haemolytic anaemia | | |

| | |frequently and have a dose-response |and hypomagnesaemia were noted. Not enough evidence to | | |

| | |relationship with ribavirin.” |ascertain causality due to lack of control group and the fact| | |

| | | |that some patients were given steroids. | | |

| |2g IV then 1g IV every 6 h |Death: 8/144; haemolytic anaemia: 71/126. |Haemoglobin levels at admission and after treatment were |Possible harm |(2) |

| |for 4 days |Authors conclude “ribavirin is temporarily |compared. Haemolysis and fall in haemoglobin were common. Not| | |

| | |associated with significant toxicity.” |enough evidence to ascertain causality due to lack of control| | |

| | | |group and the fact that some patients were given steroids. | | |

| |0.4-0.6g/day-1 IV |Death in ribavirin and CPAP group :2/40 |Comparison made between patients given both ribavrin and |Inconclusive |(3) |

| | |Death in no ribavirin group: 9/90. |CPAP to those treated with other than ribavirin. Treatment | | |

| | |Authors conclude “no advantage seen” |regimens appear to be neither standardized nor randomized. | | |

| | | |Possible confounding by the epidemic. Cannot distinguish | | |

| | | |effect of ribavirin from other treatments. | | |

| |Not available |Abnormal liver enzyme activity after treatment |Liver function outcomes before and after treatment were |Inconclusive |(4) |

| | |in 70%. Liver enzyme activities were not |compared. Correlation of ribavirin treatment with abnormal | | |

| | |correlated with duration of treatment. Authors|liver enzyme activities not clear. Subset of patients | | |

| | |conclude “SARS might affect the liver and |treated in a different hospital may have differed in illness | | |

| | |induce damage in the course of infection” |severity. Causality unclear as no appropriate control group | | |

| | | |available and some patients were treated with steroids. | | |

| |Not available |Death: 8/120. |All patients received ribavirin, some received steroids; |Inconclusive |(5) |

| | | |without a control group treated differently, it is not clear | | |

| | | |if ribavirin was of any benefit. | | |

| |400 mg IV or 2.4 g then 1.2g |Haemolytic anemia: 49/138. |Haemoglobin levels at baseline and 2 wks after treatment were|Possible harm |(6) |

| |oral, 3 times daily |Response to ribavirin and low dose steroid |compared. Haemolytic anaemia and hyperglycaemia were common.| | |

| | |treatment: 25/107 |Causality unclear due to lack of a control group and | | |

| | | |co-treatment with steroids. | | |

| |40 mg/kg oral daily |Short-term use of ribavirin was well tolerated |Article type is a research letter. Treatment effect of |Inconclusive |(7) |

| | |and had no major short-term adverse effects |ribavirin cannot be established due to lack of a control | | |

| | |such as severe haemolytic anaemia: 10/10 |group. Good outcome may be due to mild SARS illness in | | |

| | |paediatric patients |children. | | |

| |8 mg/kg IV every 8 h for 14 |Afebrile within 48 hours of ribavirin and |Anaemia occurred in 8% but unclear if due to ribavirin, |Inconclusive |(8) |

| |days |steroids: 74/75. Fever recurred in 64/75 of |illness or co-treatment. Unclear if ribavirin of any benefit| | |

| | |patients at a mean of 8.9 days. |due to lack of control group. | | |

| | |Death: 5/75 | | | |

| |8 mg/kg IV 3 times/day or 1.2|Good response: 17/40, Fair response: 9/40 Poor|SARS confirmed by serology. Treatment response determined at |Inconclusive |(9) |

| |g oral 3 times/day |response : 14/40. Three distinct categories of|5 days post treatment. Pre-determined outcome categories were| | |

| | |patients who differ in treatment response and |“good, fair, poor.” Unclear if ribavirin of any benefit since| | |

| | |severity of disease at presentation. |all received steroids and lack of control group. | | |

| |8 mg/kg IV every 8 h. If |Illness progression: 208/323. Many patients |SARS confirmed by serology. Authors found patients who |Inconclusive |(10) |

| |extensive pneumonitis: |progressed to pneumonitis despite ribavirin and|sought treatment early and received ribavirin and steroid | | |

| |loading dose of 33 mg/kg |steroid combination therapy. |combination therapy did not benefit compared to those who | | |

| |followed by 20mg/kg every 8 |Death: 26/323 |sought treatment later. Early treatment-seekers were given | | |

| |h. or oral equivalent. | |antivirals later in illness. Unclear if ribavirin of any | | |

| | | |benefit due to lack of a control group. | | |

| |8mg/kg IV every 8 h. one |Empirical treatment with a combination of |No information on how many patients improved following |Inconclusive |(11) |

| |patient received oral 1.2g |high-dose corticosteroid and ribavirin |ribavirin treatment. Benefit or harm cannot be determined | | |

| |every 8 h. |coincided with clinical improvement. |due to very small sample size of 10. | | |

| |400 mg IV every 8 h for 14 |Death: 42/109 |High mortality in this cohort. Unclear if ribavirin of any |Inconclusive |(12) |

| |days. Or oral: 1.2 g 3 times|Raised serum LD1 level was a predictor of death|benefit or harm due to lack of a control group. | | |

| |daily after leading dose of |in a multiple ROC curve comparison of | | | |

| |2.4g. |prognostic indicators. A haemolytic effect of | | | |

| | |ribavirin cannot be excluded as a possible | | | |

| | |cause. | | | |

| |1.2 g oral 3 times/day. If |Death: 5/138 |Unclear if ribavirin of any benefit or harm due to lack of a |Inconclusive |(13) |

| |worsened then 400 mg IV every|Respiratory failure: 32/138 |control group. | | |

| |8 hours. | | | | |

| |Not available |Liver dysfunction: 29.6% before ribavirin and |Study compared biochemical levels in SARS patients pre- and |Possible harm |(14) |

| | |75.9% during treatment. Liver dysfunction is a |post- treatment. Also compared levels to patients without | | |

| | |distinct abnormality in patients with SARS. |SARS. Data regarding dosage of ribavirin is not shown. | | |

| | | |Ribavirin may have caused liver dysfunction but difficult to | | |

| | | |establish causality due to lack of control group and | | |

| | | |co-treatment with steroids. | | |

| |IV 8mg/kg tid, oral: 1.2g tid|No outcomes reported |Data is very poor quality because outcome is the current |Inconclusive |(15) |

| | | |state of patient on a single day of chart review. No control | | |

| | | |group. | | |

| |8 mg/kg IV every 8 hours for |Death: 14/54. Mortality amongst critically ill |Mortality is expected to be high because cohort consists of |Inconclusive |(16) |

| |7-10 days followed by 4 mg/kg|patients with SARS is high. |ICU patients. Lack of a control group and co-treatment with | | |

| |enterally for 11-14 days | |steroids prevents a conclusion on treatment effect. | | |

| |1.2g tid oral; or 400 mg IV |Death in ribavirin group: 10.3%; |Cox regression analysis used to compare survival time between|Inconclusive |(17) |

| |every 8 h |Death in control group: 12.3%. Hazard ratio |those given ribavirin and those not. Adjusted for predictors | | |

| | |indicated no significant difference. Authors |of poor prognosis. Treatment allocation was not randomised | | |

| | |acknowledge limitations but suggest that |and bias may have affected the results. Groups were treated | | |

| | |ribavirin confers no benefit. |at different times of the epidemic, ribavirin group treated | | |

| | | |earlier. | | |

| |2.0g oral then 100-1200 mg |Death: 4/29. Anemia:14/29 patients. “No |No comparisons or tests of significance used. Results are |Inconclusive |(18) |

| |daily; or IV 400mg every 8h |obvious therapeutic response” to ribavirin. |anecdotal. Lack of a control group and patients also treated | | |

| | | |with steroids and immunoglobulin. | | |

| |Not available |Death: 6/62. After 18 patients received |Findings in regard to treatment are non-specific. No |Inconclusive |(19) |

| | |treatment for average of 9 days, authors note |protocol for the timing or dosage of steroids. Conclusions | | |

| | |“no clinically beneficial effect on the course |on treatment cannot be made due to lack of a control group. | | |

| | |of illness” | | | |

| |Not available |ARDS was associated with significant mortality |Study looked for associations with ARDS. Not possible to |Inconclusive |(20) |

| | |despite aggressive therapy. Lymphopenia was |determine specific treatment effect since many different | | |

| | |common and probably because of ribavirin |treatments were given together. Treatment determined by | | |

| | |therapy. |physicians and not defined by specific criteria. | | |

| |8 mg/kg 3 times/day IV for 3 |Death: 2/13. Ribavirin was of limited value in |This study compared cytokine levels in SARS patients with |Inconclusive |(21) |

| |days then 1200 mg 3 times/day|reducing proinflammatory cytokines secondarily |healthy controls of similar age and sex. | | |

| |orally for 10 days. |to neutralising the infecting virus. | | | |

| |40-60 mg/kg/day oral |Death 0/13. All patients tolerated high dose |Unclear if ribavirin is of any benefit due to lack of a |Inconclusive |(22) |

| | |ribavirin well without major side effects |control group and small sample size. | | |

| | |during a 6-week follow-up period. Results may | | | |

| | |not be directly applicable to adults. | | | |

| |20 mg/kg 3 times/day. |Death 3/20. No clinical benefit noted with |Very early report on the index case and initial contacts in |Inconclusive |(23) |

| | |ribavirin. Of note, Treatment was started late |Singapore. Outcomes not specific to treatment and lack of | | |

| | |in course of illness, 10-14 days after |control group prohibits conclusion on treatment | | |

| | |symptoms. |effectiveness. | | |

| |2,000 mg followed by 1,200 |Death 15/76. 23.1% of those who received |Lack of control group, underlying conditions in several |Inconclusive |(24) |

| |mg/day if body weight >75kg, |steroids had rebound or persistance of fever |patients and combination of treatment prevents conclusion on | | |

| |or 1,000 mg/day if body |after initial use. 18 patients developed |treatment effectiveness. | | |

| |weight ................
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